DESCRIPTION: Few, if any, issues in medicine have been more controversial than whether postmenopausal estrogen replacement (E) provides cardiovascular benefits. Much of the speculation concerns the impact of timing of postmenopausal estrogen treatment on coronary heart disease outcomes. Studies in our laboratories indicate that the stage of atherosclerosis and/or time while postmenopausal at initiation of treatment is a critical determinant of the ability of E to favorably affect arterial wall pathophysiology. E has its greatest atheroinhibitory effects in nonhuman primates early in atherosclerosis development (i.e., with coronary artery fatty streaks or initial fatty plaques), whereas with advanced atherosclerotic plaques, traditional E has few beneficial effects. Findings from our monkey studies were important in Dr. Howard Hodis1 decision to plan and initiate the Early versus Late Intervention Trial with Estradiol (ELITE), now funded by the National Institute of Aging (Grant #5R01AG024154). The proposed research is a companion study to ELITE, enabling us to conduct studies impossible to do in women, which will complement and enhance the interpretation of the ELITE data. Differential responses to E may relate to loss of vascular estrogen receptor (ER) expression in late menopause (advanced lesions), and we have observed an inverse relationship between atherosclerosis extent and ER expression in postmenopausal monkeys. We propose that atheroprotective effects of E will be dependent on the level of expression of arterial ER prior to treatment, which can be measured in monkeys but not in women. Furthermore, we propose E will have considerably different effects in advanced lesions (plaques) developed while menopausal for years compared to early lesions (fatty streaks) produced over a short menopausal period. Our approach will be to utilize histologic, immunohistologic, biochemical, and quantitative molecular methods to explore ER expression and mechanisms underlying differential effects of E (17li estradiol) on arterial biologic endpoints including lesion morphology and gene expression in surgically postmenopausal monkeys with short and long postmenopausal period before treatment (early vs. late stage atherosclerosis). The results will increase our understanding of the effects of estrogen treatment on the progression of atherosclerosis in early and late menopause, an issue of critical public health significance for women experiencing hot flushes and other menopausal symptoms faced with decisions on how to ease these problems safely without increasing the risk of adverse outcomes, such as stroke or myocardial infarction.